We report the design, synthesis and efficacy of a new class of gel-like nano-carrier, or 'nanogel', prepared via templated electrostatic assembly of anionic hyaluronic acid (HA) polysaccharides with the cationic peptide amphiphile poly-L-lysine (PLL). Small molecules and proteins present during nanogel assembly become directly encapsulated within the carrier and are precisely released by tuning the nanogel HA:PLL ratio to control particle swelling. Remarkably, nanogels exhibit versatile and complimentary mechanisms of cargo delivery depending on the biologic context. For example, in mammalian cells, nanogels are rapidly internalized and escape the endosome to both deliver membrane-impermeable protein cargo into the cytoplasm and improve chemotherapeutic potency in drug resistant cancer cells. In bacteria, nanogels permeabilize microbial membranes to sensitize bacterial pathogens to the action of a loaded antibiotic. Thus, peptide nanogels represent a versatile, readily scalable and bio-responsive carrier capable of augmenting and enhancing the utility of a broad range of biomolecular cargoes.
Liquid-in-liquid emulsions are kinetically stable colloids that undergo liquid-to-gas phase transitions in response to thermal or acoustic stimuli. Perfluorocarbons (PFCs) are preferred species as their highly fluorinated nature imparts unique properties that are unparalleled by nonfluorinated counterparts. However, traditional methods to prepare PFC emulsions lack the ability to precisely tune the thermodynamic stability of the fluorous−water interphase and consequently control their vaporization behavior. Here, we report a privileged fluoroalkanoic acid that undergoes concentration-dependent assembly on the surfaces of fluorous droplets to modulate interfacial tension. This allows for the rational formulation of orthogonal PFC droplets that can be programmed to vaporize at specified ultrasound powers. We exploit this behavior in two exemplary biomedical settings by developing emulsions that aid ultrasound-mediated hemostasis and enable bioorthogonal delivery of molecular sensors to mammalian cells. Mechanistic insights gained from these studies can be generalized to tune the thermodynamic interfacial equilibria of PFC emulsions toward designing controllable tools for precision medicine.
Although rarely used in nature, fluorine has emerged as an important elemental ingredient in the design of proteins with altered folding, stability, oligomerization propensities, and bioactivity. Adding to the molecular modification toolbox, here we report the ability of privileged perfluorinated amphiphiles to noncovalently decorate proteins to alter their conformational plasticity and potentiate their dispersion into fluorous phases. Employing a complementary suite of biophysical, in‐silico and in‐vitro approaches, we establish structure‐activity relationships defining these phenomena and investigate their impact on protein structural dynamics and intracellular trafficking. Notably, we show that the lead compound, perfluorononanoic acid, is 106 times more potent in inducing non‐native protein secondary structure in select proteins than is the well‐known helix inducer trifluoroethanol, and also significantly enhances the cellular uptake of complexed proteins. These findings could advance the rational design of fluorinated proteins, inform on potential modes of toxicity for perfluoroalkyl substances, and guide the development of fluorine‐modified biologics with desirable functional properties for drug discovery and delivery applications.
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